Cachexia, progressive wasting of adipose tissue and skeletal muscle, is a devastating condition afflicting about half of all cancer patients. Disproportionate loss of muscle protein despite adequate food intake results in reduced ambulation, diminished quality of life, poor response to therapy, and ultimately death. Indeed, cachexia itself causes the deaths of roughly 25% of all cancer patients. Pathological muscle wasting appears to result from suppression of hypertrophic pathways including the insulin-like growth factor pathway, and activation of catabolism largely through skeletal muscle specific ubiquitin ligases. Both tumor-derived factors and host-derived cytokines such as TNF, interferon-gamma and Interleukins (IL)-1 and IL-6 appear to mediate cancer cachexia. In normal development and adulthood, muscle growth is suppressed by the muscle-specific factor myostatin. We show that IL-6 and myostatin both induced myotube wasting in vitro and profound wasting of muscle and adipose tissue in vivo. Analysis of signaling pathways and gene expression demonstrated induction of the STAT3 pathway and downstream target genes by both IL-6 and myostatin. IL-6 and myostatin markedly induced genes predicted to inhibit the IGF pathway and promote proteolysis. Consistent with a role in cachexia, STAT3 was activated in five mouse models of muscle wasting due to cancer or prolonged sepsis. Moreover, STAT3 activation was sufficient to induce wasting in normal skeletal muscle, while STAT3 inhibition blocked IL-6-induced wasting. Thus STAT3 represents a novel therapeutic target for potential treatment of muscle wasting in cachexia due to cancer, sepsis, burn, AIDS, organ failure or other chronic disease. The objectives of this project are to define the role of the STAT3 pathway on muscle growth and wasting, to identify the downstream effectors leading to wasting, and to target the STAT3 pathway for potential muscle preservation in cancer cachexia. The specific aims are to 1) dissect the molecular pathways from IL-6 and myostatin signaling through STAT3 to muscle wasting using C2C12 myofiber cultures;2) define the contribution of STAT3 and downstream targets SOCS3 and TC-PTP/PTPN2 in muscle growth regulation and wasting using gene transfer in intact mouse skeletal muscle, and 3) determine the role of skeletal muscle SOCS3 expression in muscle growth regulation and wasting using transgenic mice. These studies are an essential step towards understanding the pathological basis of cancer cachexia and will contribute to development of therapies aimed at preserving muscle mass and improving and prolonging life. PUBLIC HEALTH RELEVANCE: Muscle wasting in cancer and other chronic diseases contributes to decreased quality of life, reduced response to therapy and mortality. We have identified a new molecular pathway leading to muscle wasting. Understanding the molecular workings of that pathway is essential to develop muscle preserving therapies.